J Pharmacol Sci 123, 1 – 8 (2013) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Current Perspective The Linkage Between Coenzyme A Metabolism and Inflammation: Roles of Pantetheinase Takeaki Nitto1,* and Kenji Onodera1,2 1Laboratory of Pharmacotherapy, Yokohama College of Pharmacy, Yokohama, Kanagawa 245-0066, Japan 2Department of Clinical Pharmacology, Epilepsy Hospital Bethel, Iwanuma, Miyagi 989-2455, Japan Received April 3, 2013; Accepted June 30, 2013 Abstract. Pantetheinase is an enzyme hydrolyzing pantetheine, an intermediate of the coenzyme A degradation pathway. Pantetheinase has long been considered as the enzyme that recycles pantothenic acid (vitamin B5) generated during coenzyme A breakdown. Genetic analyses showed that mammals have multiple genes known as vanin family genes. Recent studies using mice lacking the vanin-1 gene (pantetheinase gene) suggest that pantetheinase is actively involved in the progression of inflammatory reactions by generating cysteamine. Additional studies using human leukocytes demonstrate that human neutrophils have abundant pantetheinase proteins on the surface and inside the cells. The second pantetheinase protein, GPI-80/VNN2, is suggested to work as a modulator of the function of Mac-1 (CD11b/CD18), an adhesion molecule important to neutrophil functions. This review delineates the characteristics of the pantetheinase/vanin gene family and how they affect inflammation. Keywords: inflammation, pantetheinase, cysteamine, neutrophil, oxidative stress 1. Introduction reverse of the biosynthetic pathway except that 4′- phosphopantetheine is converted to pantetheinase fol- Inflammation is the protective response by the host lowed by conversion to pantothenic acid by the pante- organism that ultimately rids injured tissues of both the theinase enzyme (Fig. 1) (2). Recent research on CoA cause and the consequences of injury (1). The cardinal metabolic enzymes has led to the discovery of uniquely signs of acute inflammation are dolor, calor, and rubor, non-metabolic roles for both enzymes and their metabo- which if not resolved in a timely manner lead to chronic lites. Pantetheinase and its product cysteamine appear to inflammation, scarring, and eventual loss of the tissue be inflammatory enhancers. and/or organ function (1). It is now evident that beyond “Pantetheinase” activity was first identified in the established inflammatory diseases such as psoriasis and crude horse kidney extracts by its ability to cleave arthritis, chronic inflammation governs the symptoms pantethine, an oxidized form of pantetheine, into panto- and pathogeneses of other prevalent diseases including thenic acid and cysteamine (3). Pantetheinase, as a cardiovascular and cerebrovascular disease, cancer, purified enzyme was later isolated from horse kidneys obesity, and Alzheimer’s disease. (4). Protein sequence comparisons of the pantetheinase Coenzyme A (CoA) has long been recognized as an to other proteins established that it is a homolog to the essential cofactor of biochemical reactions such as car- protein vanin-1 in mice (5). In mice, three genes related boxylic acid metabolism, including short- and long-chain to pantetheinase are recorded in international databases fatty acids in various organisms (2). CoA is generated (5 – 10). In this review, we discuss recent studies about from pantothenic acid (vitamin B5) through a series of pantetheinase and its roles in inflammatory diseases. five synthetic reactions. CoA catabolism occurs as the Pantetheinase function has been primarily investigated in both vanin-1–deficient mice and human leukocytes. *Corresponding author. [email protected] We also discuss the possibility of cysteamine’s involvement Published online in J-STAGE on August 24, 2013 doi: 10.1254/jphs.13R01CP in inflammation and potential novel anti-inflammatory drugs that modify pantetheinase activity. Invited article 1 2 T Nitto and K Onodera Fig. 1. Metabolic and synthetic pathway of co- enzyme A (CoA). Schematic of metabolic pathway of CoA is indicated with downward arrows. CoA is dephosphorylated at the 3′ position of ribose to form dephosphoCoA. DephosphoCoA is then de- graded to 4′-phosphopantetheine and 5′-AMP. Dephosphorylation of 4′-phosphopantetheine forms pantetheine. In the final step in the metabolic pathway, panthetheine is degraded to pantothenic acid (vitamin B5) and cysteamine (b-mercapto- ethylamine) by pantetheinase. Since pantothenic acid generated during the CoA degradation is re- cycled for another biosynthesis of CoA (indicated by upward arrows), the step of hydrolysis of pante- theine by pantetheinase is important for the “sal- vage pathway” of CoA biosynthesis. ATP, adenos- ine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; PPi; pyrophos- phate; Pi, phosphate. Table 1. Pantetheinase gene family in human and mouse Human (located at locus 6q23-24) Gene name length (kbp) Tissue expression profile VNN1, Pantetheinase 32.4 spleen, small intestine, peripheral blood leukocyte, liver VNN2, GPI-80 14.0 neutrophils, monocytes, colon, spleen, placenta, lung VNN3 12.0 spleen, peripheral blood leukocyte, liver Mouse (located at the locus 10A2B1) Gene name length (kbp) Tissue expression profile Vanin-1, Pantetheinase 10.6 kidney, small intestine, liver, testis, heart Vanin-3 18.4 spleen, peripheral blood leukocyte, liver, kidney, thymus, heart Summary of the comparison of the five pantetheinase genes focusing on gene names, locus in human and mouse, gene length (kilo base pairs), and the tissues in which the five genes are mainly expressed. 2. Pantetheinase gene family activity that hydrolyzes pantetheine into pantothenic acid and cysteamine. Mouse pantetheinase/vanin-1 is 2.1. Pantetheinase/vanin-1/VNN1 produced as a glycosylphosphatidyl inositol (GPI)- Vanin-1 was first identified as the molecule recognized anchored protein and is located on the plasma membrane by a monoclonal antibody to murine thymic stromal cell of epithelial cells. In addition, the pantetheinase protein line (6), which regulates adhesion of the thymocytes and was shown to be expressed in the human kidney. The thymus homing. The vanin-1 genes have been identified mouse vanin-1 functions are best documented, since in mouse, human, rat, chicken, and 16 other organisms vanin-1–deficient mice have been generated and ana- according to the NCBI database. Regarding mice lyzed (see below). and humans, the pantetheinase/vanin gene family are clustered on chromosome 10A2B1 of mice (7, 10), and 2.2. GPI-80/VNN2 the human analog (VNN1) is on chromosome 6q23-24 Humans have two pantetheinase-related genes, GPI- (7, 8) (Table 1). Although the murine vanin-1 was first 80/VNN2 and VNN3. Galland et al. (7) identified two cloned from a thymic stromal cell line, the expression human cDNAs homologous to mouse vanin-1 during the of vanin-1 mRNA is also found in the small intestine, screening of human kidney, liver, and placental cDNA kidney, liver, and other immunological tissues (11) libraries; the two genes are named VNN1 and VNN2 (Table 1). Mouse vanin-1 is induced by the activation after the mouse vanin-1 gene. Suzuki et al. (9) identified of two antioxidant response elements in epithelial cells a protein recognized by the monoclonal antibody, (12). On the other hand, the pantetheinase protein was 3H9, which modulated adhesion and transmigration of purified from porcine kidney by tracing the enzymatic activated human neutrophils; this protein was named Roles of Pantetheinase on Inflammation 3 GPI-80 (80-kDa protein with GPI-anchor). It was later 3. Roles of pantetheinase in the regulation of inflam- determined that Suzuki and Galland had independently mation in vivo identified the same gene, GPI-80/VNN2. Queries of the mouse genome have not uncovered a homologue 3.1. Vanin-1 deficient mice of GPI-80/VNN2, suggesting that the gene was divided Among the three proteins belonging to the pantetheinase from the common orthologue of vanin-1/VNN1 and gene family, pantetheinase/vanin-1/VNN1 has been best GPI-80/VNN2 during evolution from rodents to pri- characterized in physiological and pathophysiological mates. The amino acid sequences of the potential amido- conditions by using vanin-1–deficient mice (summarized hydrolase active center are conserved between human in Table 2). Vanin-1–deficient mice lack detectable VNN1 (pantetheinase) and GPI-80/VNN2. GPI-80/VNN2 cysteamine (11), one of the metabolites of pantetheine, was determined to have pantetheinase enzymatic suggesting that vanin-1 is the major enzyme for pante- activity (10), but the activity is weaker than that of theine hydrolyzation in mice. Vanin-1–deficient mice VNN1. Finally, both pantetheinase/vanin-1/VNN1 and exhibit resistance to apoptotic oxidative tissue injury GPI-80/VNN2 are biosynthesized as GPI-anchored pro- caused by g-irradiation or by the administration of tein. GPI-80/VNN2 mRNAs are expressed in leukocytes, paraquat (12). They also show an attenuated inflam- colon, spleen, placenta, and lung. The expression of matory bowel reaction in response to the administration GPI-80/VNN-2 increases in neutrophil progenitors of non-steroidal anti-inflammatory drugs (17) or 2,4,6- during both differentiation and maturation (13). trinitrobenzene sulfonic acid (18) and to Schistosoma manosoni infection (17). Administration of peroxisome 2.3. Vanin-3/VNN3 proliferator-activated receptor (PPAR) g antagonist in- Vanin-3 in mouse and VNN3 in humans have some- hibited the alleviation of the inflammation (18), suggest- what different